Daraprim

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Daraprim

WARNINGS

The dosage of pyrimethamine required for the treatment of toxoplasmosis is
10 to 20 times the recommended antimalaria dosage and approaches the toxic level.
If signs of folate deficiency develop (see ADVERSE REACTIONS), reduce
the dosage or discontinue the drug according to the response of the patient.
Folinic acid (leucovorin) should be administered in a dosage of 5 to 15 mg daily
(orally, IV, or IM) until normal hematopoiesis is restored.

Data in 2 humans indicate that pyrimethamine may be carcinogenic: a 51-year-old
female who developed chronic granulocytic leukemia after taking pyrimethamine
for 2 years for toxoplasmosis,3 and a 56-year-old patient who developed
reticulum cell sarcoma after 14 months of pyrimethamine for toxoplasmosis.4

Pyrimethamine has been reported to produce a significant increase in the number
of lung tumors in mice when given intraperitoneally at doses of 25 mg/kg.5

DARAPRIM (pyrimethamine) should be kept out of the reach of infants and children as they are
extremely susceptible to adverse effects from an overdose. Deaths in pediatric
patients have been reported after accidental ingestion.

PRECAUTIONS

General

The recommended dosage for chemoprophylaxis of malaria should not be exceeded.
A small “starting” dose for toxoplasmosis is recommended in patients with convulsive
disorders to avoid the potential nervous system toxicity of pyrimethamine. DARAPRIM (pyrimethamine)
should be used with caution in patients with impaired renal or hepatic function
or in patients with possible folate deficiency, such as individuals with malabsorption
syndrome, alcoholism, or pregnancy, and those receiving therapy, such as phenytoin,
affecting folate levels (see Pregnancy subsection).

Laboratory Tests

In patients receiving high dosage, as for the treatment of toxoplasmosis,
semiweekly blood counts, including platelet counts, should be performed.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Mutagenesis: Pyrimethamine has been shown to be nonmutagenic
in the following in vitro assays: the Ames point mutation assay, the
Rec assay, and the E. coli WP2 assay. It was positive in the L5178Y/TK
+/- mouse lymphoma assay in the absence of exogenous metabolic activation.6
Human blood lymphocytes cultured in vitro had structural chromosome aberrations
induced by pyrimethamine.

In vivo, chromosomes analyzed from the bone marrow of rats dosed with
pyrimethamine showed an increased number of structural and numerical aberrations.

Pregnancy

Teratogenic Effects: Pregnancy Category C. Pyrimethamine has
been shown to be teratogenic in rats when given in oral doses 7 times the human
dose for chemoprophylaxis of malaria or 2.5 times the human dose for treatment
of toxoplasmosis. At these doses in rats, there was a significant increase in
abnormalities such as cleft palate, brachygnathia, oligodactyly, and microphthalmia.
Pyrimethamine has also been shown to produce terata such as meningocele in hamsters
and cleft palate in miniature pigs when given in oral doses 170 and 5 times
the human dose, respectively, for chemoprophylaxis of malaria or for treatment
of toxoplasmosis.

There are no adequate and well-controlled studies in pregnant women. DARAPRIM (pyrimethamine) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Concurrent administration of folinic acid is strongly recommended when used for the treatment of toxoplasmosis during pregnancy.

Nursing Mothers

Pyrimethamine is excreted in human milk. Because of the potential for serious
adverse reactions in nursing infants from pyrimethamine and from concurrent
use of a sulfonamide with DARAPRIM (pyrimethamine) for treatment of some patients with toxoplasmosis,
a decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the mother (see WARNINGS
and PRECAUTIONS: Pregnancy ).

Pediatric Use

Geriatric Use

Clinical studies of DARAPRIM (pyrimethamine) did not include sufficient numbers of subjects
aged 65 and over to determine whether they respond differently from younger
subjects. Other reported clinical experience has not identified differences
in responses between the elderly and younger patients. In general, dose selection
for an elderly patient should be cautious, usually starting at the low end of
the dosing range, reflecting the greater frequency of decreased hepatic, renal,
or cardiac function, and of concomitant disease or other drug therapy.